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Hypertonicity increases CLC-5 expression in mouse medullary thick ascending limb cells

¹Renal Division, Department of Medicine, Olive View-UCLA Medical Center, Sylmar 91342; ³Kidney and Pancreas Transplantation, Department of Medicine, David Geffen UCLA Medical Center, Los Angeles 90095; ⁴Renal Division, Department of Medicine, Sepulveda Veterans Administration Medical Center, Sepulveda, California 91343; and ²Division of Nephrology, Universite Catholique de Louvain, B-1200 Brussels, Belgium

Submitted 23 June 2003 ; accepted in final form 17 May 2004

Genetic studies indicated that mutations of the chloride channel CLC-5 in the kidney are responsible for a group of clinical disorders, collectively called Dent's disease. In the kidney, CLC-5 was found to be expressed in the proximal tubule, medullary thick ascending limb (mTAL) of loop of Henle, and intercalated cells of the collecting tubule. In proximal tubular cells, CLC-5 was found to play an important role in receptor-mediated endocytosis. However, the functional roles of CLC-5 in mTAL and collecting tubules remain unclear. Because mTAL is normally exposed to a hypertonic environment, we aimed to examine the effect of hypertonicity on CLC-5 expression in this nephron segment. Our studies revealed that exposure to hypertonicity (up to 550 mosM) increased CLC-5 mRNA and protein levels in a murine mTAL cell line (MTAL) but not in an opossum kidney (OK) proximal tubular cell line. A similar effect was also found in mouse kidneys, where CLC-5 expression was enhanced in renal medulla, but not cortex, after 48 h of water deprivation. We also tested the effect of hypertonicity on endocytotic activity and found that exposure to hypertonicity caused a significant decrease in cellular uptake of FITC-labeled albumin in OK but not in MTAL cells. Our results suggest that CLC-5 expression is upregulated by hypertonicity in mTAL cells but not in proximal tubular cells. We speculate that the increased CLC-5 levels in mTAL may serve to maintain the endocytotic activity in a hypertonic environment.

chloride channels; water deprivation; endocytosis

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				M. Ludwig, B. Utsch, and L. A. H. Monnens Recent advances in understanding the clinical and genetic heterogeneity of Dent's disease Nephrol. Dial. Transplant., October 1, 2006; 21(10): 2708 - 2717. [Full Text] [PDF]